Dietary restriction (DR), or reduced food intake without malnutrition, is highly beneficial in a variety of experimental organisms using a number of endpoints, including glucose homeostasis, acute stress resistance and longevity. While energy restriction is commonly thought to the key to a successful DR regimen, a small but growing body of literature points to the dominant role of nutrient restriction. Long-term restriction of dietary methionine, an essential amino acid, results in increased lifespan, health span and acute stress resistance in experimental rodents. Although the phenotype resembles that of DR, it occurs in the absence of energy restriction. The benefits of methionine restriction are thought to involve perturbation of one or more methionine-requiring pathways, such as DNA methylation or glutathione biosynthesis. Our preliminary data indicate that short-term restriction of dietary methionine improves glucose homeostasis and stress resistance within as little as six days. Importantly, we have also found that restriction of two other essential amino acids - tryptophan and leucine - lend similar benefits. We hypothesize that restriction of any essential amino acid will rapidly trigger changes in animal physiology resulting in improved glucose homeostasis and increased stress resistance. Our aim is to elucidate relevant upstream amino acid sensing pathways and downstream effectors of oxidative stress resistance with the ultimate goal of translating these benefits to the clinic. PUBLIC HEALTH RELEVANCE: Long-term methionine restriction increases lifespan, health span and stress resistance in experimental rodents. Here we propose to test the ability of short-term methionine restriction to increase stress resistance and improve insulin sensitivity in mice. Our aim is to elucidate upstream nutrient sensing pathways and downstream effectors with the ultimate goal of translating these benefits to the clinic.